Vasoocclusion is responsible for much of the morbidity and mortality of Sickle Cell Disease (SCD). Abnormal red cell (RBC) rheology, resulting from polymerization of deoxy Hb S, is thought to be the primary basis of vasoocclusion, but there is considerable evidence that other RBC, humoral and endothelial cell factors play important modulating roles. The presence of endothelial cell damage, abnormalities in soluble and cellular components of the coagulation system, and thrombi in tissues of SCD patients suggest the hypothesis that thrombosis contributes to vasoocclusion in SCD. The availability of transgenic mouse models for SCD provides a unique opportunity for genetic manipulation of the coagulation system to test this hypothesis. The SAD-1 transgenic mouse line expresses the sickling Hb SAD and exhibits, under conditions of ambient oxygen, pathologic features of SCD similar to human patients, including significant thrombotic vasoocclusive events. In Specific Aim I of this proposal, the SAD mouse line will be crossed with each of three recently developed transgenic lines which have: 1) no circulating fibrinogen due to disruption of the Aa-chain gene (Aa-/-); 2) a truncation of the fibrinogen gamma chain, which ablates platelet aggregation (gamma-delta5+/+); 3) no circulating plasminogen due to gene disruption (Plg-/-). If the hypothesis is true that fibrinogen-dependent functions (fibrin clot formation and platelet aggregation) contribute to the vasoocclusive process in SCD, the pathological manifestations of SCD in SAD mice should be ameliorated in the SAD/Aa-/- animals. Likewise, the evaluation of the SAD/gamma-delta5 mice will test a similar hypothesis about the role of fibrinogen-dependent platelet aggregation, as distinct from fibrin clot formation. In contrast, the SAD/Plg-/-mice will reveal the postulated role of coagulation in SCD by manifesting worsened vasoocclusive pathology due to deficiency in fibrinolysis. The hematologic consequences of the combined SAD and coagulation deficiencies will be evaluated in Specific Aim 2 with measurements of coagulation function; Hb SAD content, oxygen affinity and blood viscosity; RBC indices, cell density and cation content; RBC and platelet survival. The severity of SCD pathology in each genotype will be evaluated in Specific Aim 3 by assessment of morbidity and mortality (survival); development of renal dysfunction; gross and microscopic pathology; sensitivity to hypoxia. The results of these genetic manipulations of coagulation on SCD pathology in the SAD mouse will elucidate the role of thrombosis in sickle cell vasoocclusion and will provide a foundation for the application of new anticoagulant, anti- platelet, and thrombolytic therapies to the treatment of sickle cell patients.